Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions.
Conventional tissue adhesives include fibrin sealants, cyanoacrylate based sealants, and other synthetic sealants and polymerizable macromers. Some of these conventional sealants are only suitable for a specific range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are expensive, often need refrigerated storage, are slow curing, have limited mechanical strength, and pose a risk of viral infection.
For certain applications, for example, ophthalmic applications such as sealing wounds resulting from trauma such as corneal lacerations, or from surgical procedures such as vitrectomy procedures, abdominal hernias, cataract surgery, LASIK surgery, glaucoma surgery, and corneal transplants; neurosurgery applications, such as sealing the dura; plugging to seal a fistula or the punctum, slow degrading tissue adhesives are needed.
The last decade, several types of (semi)synthetic hydrogel tissue adhesives have been developed, which have improved adhesive properties and are non-toxic. Most of these hydrogel tissue adhesives, like DuraSeal®, are chemically based on a process called PEGylation used in polymer-modified therapeutics with reactive polyethylene glycol (PEG) precursors like, for instance, PEG-succinimidyl glutarate. These hydrogel tissue adhesives, based on PEGylation, typically swell or dissolve away too quickly, or lack sufficient cohesion (interconnecting mechanical strength), thereby decreasing their effectiveness as surgical adhesives. Moreover, to apply these hydrogel tissue adhesives, dual syringe spray technology may be needed, which demands extensive sample preparation from freeze dried starting materials. Finally, the properties of such PEG-based materials cannot be easily controlled and the number of NHS-groups is limited to the number of chain ends; possibly comprising multiple NHS groups per chain end resulting in a high NHS group density rather than regularly distributed groups.
WO 2002/062276 describes a hydrogel tissue sealant comprising a star-shaped PEG-succinimidyl glutarate precursor, also known as star-PEG-NHS or star-PEG-NS or star-SG-PEG or star-PEG-SG, that reacts with a trilysine precursor. The star-SG-PEG precursor may be reconstituted in pH 4 phosphate, while the trilysine precursor may be reconstituted in pH 8 borate buffer. Upon mixing, covalent amide bonds between amines of the trilysine precursor and NHS-activated terminal carboxylate groups of the star-SG-PEG precursor are formed.
WO 2010/059280 describes an anhydrous fibrous sheet comprising a first component of fibrous polymer, said polymer containing electrophilic groups or nucleophilic groups, and a second component capable of crosslinking the first component when said sheet is exposed to an aqueous medium to form a crosslinked hydrogel that is adhesive to biological tissue. The examples of the international patent application describe the preparation of fibrous sheets comprising dextran aldehyde and multi-arm polyethylene glycol amine.
WO 00/33764 describes a method for preparing a biocompatible crosslinked polymer, comprising:                providing a biocompatible small molecule crosslinker having n crosslinker functional groups, wherein n is two or more, and wherein the crosslinker functional groups are either electrophilic or nucleophilic;        dissolving the biocompatible small molecule crosslinker in a first solvent to form a crosslinker solution;        providing a biocompatible functional polymer having m functional polymer functional groups, wherein m is two or more and the sum of n and m is five or more, and wherein the functional polymer functional groups are nucleophilic if the crosslinker functional groups are electrophilic, and the functional polymer functional groups are electrophilic if the crosslinker functional groups are nucleophilic;        dissolving the biocompatible functional polymer in a second solvent to form a functional polymer solution; and        combining the crosslinker and functional polymer solutions to react the crosslinker functional groups with the functional polymer functional groups.Polyoxazoline is nowhere mentioned in WO 00/33764.        
WO 2005/109248 describes cross-linked polymeric compositions of hydrolyzed poly (2-alkyl-2-oxazoline) and the use of these cross-linked polymeric compositions in color ink-jet ink.
WO 2009/043027 describes multiarmed, monofunctional derivatives of polyoxazolines, as well as conjugates of such polyoxaline derivatives with drugs.
Preparation of a cross-linked, polymer by reacting nucleophilically activated polyoxazoline (NU-POX) with an electrophilically activated cross-linking agent has been described by Luxenhofer (Thesis: Novel Functional Poly(2-oxazoline)s as Potential Carriers for Biomedical Applications, Technische Universitat München (2007)). A poly(2-oxazoline) comprising 20 units of 2-methyl-2-oxazoline and 5 units of 2-aminoethyl-2-oxazoline was cross-linked with hexamethylene diisocyanate. Due to the high reactivity of isocyanates towards water, the hydrogel preparation had to be performed in the absence of water. As a good and water compatible (for subsequent swelling) solvent for poly(2-oxazoline)s acetonitrile was chosen. The cross-linker was directly added to the solvent which was subsequently added to the lyophylized polymer. After 10 min 1.5 mL of water was added upon which the hydrogel immediately swelled.
Chujo et al. (Reversible Gelation of Polyoxazoline by Means of Diels-Alder Reaction, Macromolecules, 1990(23), 2636-2641) describes the preparation of a polyoxazoline hydrogel by means of intermolecular Diels-Alder reaction between furan-modified poly(N-acetylethylenimine) (PAEI) and maleimide-modified PAEI, which were synthesized from the partially hydrolyzed PAEIs by the reaction with furan- or maleimidecarboxylic acid, respectively, in the presence of dicyclohexylcarbodiimide.
It is of interest to expand the range of polymers having implant or tissue sealant applications, especially to provide polymers having properties not possessed by PEG-based polymers while being similarly biocompatible.